The proliferation and differentiation of cells in multicellular organisms is subject to a highly regulated process. A distinguishing feature of cancer cells is the absence of control over this process; proliferation and differentiation become deregulated resulting in uncontrolled growth. MicroRNAs (miRNAs) are important regulators of gene expression and can play crucial roles during development and differentiation.
Hematopoiesis is a highly structured differentiation process in which tight control of gene expression is required for proper generation of mature blood cells. The coordinated control of gene expression is exerted at multiple levels. External signals from the microenvironment can drive the differentiation of hematopoietic stem cells (HSC) towards different lineages. In addition, the expression levels of particular transcription factors are key determinants for differentiation to several lineages.
Hematopoietic malignancies are malignant blood diseases including various lymphomas and leukemias. Leukemias result from disruption of differentiation of early blood cell precursors that proliferate uncontrollably and fail to develop into mature cells. Pharmacological agents that induce terminal differentiation of cancer cells have been used to treat some leukemias. Furthermore, these agents have allowed the development of suitable model systems to study hematopoiesis. However, the molecular mechanisms that govern differentiation of normal and leukemic blood cells are still poorly understood.
Leukemic cell lines have been routinely used as models to study hematopoietic cell differentiation in vitro. The human erythroleukemia cell line K562, which was derived from a patient with chronic myelogenous leukemia (CML), resembles a bipotent megakaryocytic-erythroid progenitor since it can undergo differentiation to both cell lineages depending on the stimulus. Phorbol esters such as 12-O-tetradecanoyl-phorbol-13-acetate (TPA) induce megakaryocytic differentiation while other agents such as hemin, sodium butirate or Ara-C induce differentiation to erythrocytes. TPA-induced megakaryocytic differentiation of leukemic K562 cells is accompanied by characteristic changes in cell morphology, cell adhesion, cell cycle arrest, endomitosis and expression of megakaryocyte lineage-specific markers such as platelet-derived growth factor and integrins αIIbβ3 (CD41/CD61) and α2β1 (CD49b).
There is an unmet need for new compositions and methods for inhibiting the growth of hematopoietic malignant cells.